Blood-spinal Cord Barrier Compromised In Mice With ALS

Date:

November 27, 2007

Source:

Public Library of Science

Summary:

The blood-spinal cord barrier is functionally impaired in areas of motor neuron damage in mice modeling amyotrophic lateral sclerosis, report researchers. The barrier disruption was found in mice at both early and late stages of ALS, a progressive neurodegenerative disease affecting nerve cells in the brain and the spinal cord.

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In the cervical spinal cord, EB was clearly detected within the blood vessels (red, arrowheads) in the control C57BL/6J mice at (A, B, C) 12–13 weeks of age or (D, E) in the lumen of vessels (brilliant green) at 19–20 weeks of age. In G93A mice, vascular leakage of EB (red, arrows) was detected (F, G) at early (13 weeks of age) disease symptoms and (H, I, J) at end-stage of disease (17–18 weeks of age) when more EB extravasation was seen. Arrowheads in F and I indicate vessel permeability. Scale bar in A–J is 25 µm.

In the cervical spinal cord, EB was clearly detected within the blood vessels (red, arrowheads) in the control C57BL/6J mice at (A, B, C) 12–13 weeks of age or (D, E) in the lumen of vessels (brilliant green) at 19–20 weeks of age. In G93A mice, vascular leakage of EB (red, arrows) was detected (F, G) at early (13 weeks of age) disease symptoms and (H, I, J) at end-stage of disease (17–18 weeks of age) when more EB extravasation was seen. Arrowheads in F and I indicate vessel permeability. Scale bar in A–J is 25 µm.

The blood-spinal cord barrier is functionally impaired in areas of motor neuron damage in mice modeling amyotrophic lateral sclerosis (ALS), report researchers at the University of South Florida Center for Aging and Brain Repair. The barrier disruption was found in mice at both early and late stages of ALS, a progressive neurodegenerative disease affecting nerve cells in the brain and the spinal cord.

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) control the exchange of substances between the blood and the central nervous system. These barriers, formed by cells lining the blood vessels in the brain and the spinal cord, protect nerve cells by restricting entry of potentially harmful substances and cells of the immune system. Impairment in cellular machinery of the BBB and BSCB may lead to a barrier breakdown in many brain and spinal cord diseases or injuries.

"We detected vascular leakage in the cervical and lumbar spinal cord microvessels of ALS mice not only at the end-stage of disease but also in those with early disease symptoms," said lead author Svitlana Garbuzova-Davis, PhD, DSc, assistant professor in the USF Center for Aging and Brain Repair. "This may suggest that large molecules such as the antibody IgG and other blood proteins appear in the spinal cord due to vascular leakage, one possible mechanism accelerating motor neuron damage."

However, Dr. Garbuzova-Davis said, questions remain: "Is the BCSB altered before disease symptoms and other pathological processes begin in ALS, and does the protective barrier's breakdown play a primary role in the development of ALS?"

"If this finding translates to ALS patients, then it should yield important ways of developing new treatments that focus on drugs or cell therapies designed to repair the BSCB," said Paul R. Sanberg, PhD, DSc, co-author and director of the USF Center for Aging and Brain Repair.

The research builds upon another USF study published earlier this year in the journal Brain Research. Using electron microscopy to examine the capillary structure of the BBB and BSCB, the researchers demonstrated extracellular edema and physical damage to capillary endothelial cells, motor neurons, and astrocytes surrounding vessels in mice with early and late ALS symptoms.

In the most recent study, the researchers examined the functional competence of the BSCB in ALS mice. They intravenously injected a blue dye tracer into mice in different stages of ALS. Vascular leakage of the dye was found in mice with initial signs of ALS such a tremor, weight loss and reduced hindlimb extension and in mice with complete hindlimb paralysis at the terminal stage of ALS. Furthermore, the study found decreased expression of the glucose transporter Glut-1 and immunological markers CD146 for endothelial cells and GFAP for astrocytes, which may relate to vascular leakage.

The USF researchers plan to investigate whether the BSCB and BBB are altered in patients suffering from ALS.

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